Peripheral Immunosuppression Research Articles

Ventilator-induced lung injury and multiple system organ failure: a critical review of facts and hypotheses.

To review how biotrauma leads to the development of multiple system organ failure (MSOF). Published articles on experimental and clinical studies and review articles in the English language were collected and analyzed. The concept that ventilation strategies using "large" tidal volumes and zero PEEP of injured lungs can enhance injury by the release of inflammatory mediators into the lungs and circulation, a mechanism that has been called biotrauma, is supported by evidence from experimental models ranging from mechanically stressed cell systems, to isolated lungs, intact animals, and humans. Biotrauma may lead to MSOF via spillover of lung-borne inflammatory mediators into the systemic circulation. However, spillover of other agents such as bacteria and soluble proapoptotic factors may also contribute to the onset of MSOF. Other less well studied mechanisms such as peripheral immunosuppression and translocation of bacteria and/or products from the gut may play an important role. Finally, genetic variability is a crucial factor. The development of MSOF is a multifactorial process. Our proposed mechanisms linking mechanical ventilation and MSOF suggest several novel therapeutic approaches. However, it will first be necessary to study the mechanisms described above to delineate more precisely the contribution of each proposed factor, their interrelationships, and their time course. We suggest that scientific advances in immunology may offer novel approaches for prevention of MSOF secondary to ventilator-induced lung injury.

Is nonmyeloablative stem cell transplantation (Nst) Associated with increased risk of delayed hemolysis?

Increased risk of delayed hemolysis following conventional minor ABO mismatched allogeneic bone marrow transplantation (BMT) has been found to be associated with peripheral blood stem cell transplantation (PBSCT), non-T-cell depletion, and immunosuppression by Cyclosporin A (CSA) or FK506. We recently demonstrated that it is possible to achieve stable engraftment with mixed or complete chimerism using nonmyeloablative conditioning consisting of Fludarabine, Busulfan and ATG followed by G-CSF mobilized PBSCT, with CSA as the sole anti-GVHD prophylaxis. Four patients (pts.) who under went NST and developed delayed hemolysis are reviewed here. All were male, of median age 18 (4–56) years. Two suffered from βThalassemia major, 1 from AML, and 1 from CML. Three were transplanted from fully matched sibling donors (2 male, 1 female), and one from a 1 locus mismatched family-related female donor. All pts. engrafted with mixed (n=3) or complete (n=1) chimerism. The donors' engrafted with mixed (n=3) or complete (n=1) chimerism. The donors' blood groups were A− (n=2), A+ (n=1) and B+ (n=1), while the recipients' were B−, A+, O+ and AB+, respectively. Clinically significant hemolysis occurred at day 173 (66–240) post-NST. Hemoglobin dropped to 5.3 (5.2–6.3) g/dL, hematocrit to 15.4 (15.3–18.9) %, with 4.1 (2.7–7.8) reticulocytes. All pts. had hyperbilirubinemia and increased LDH levels. Their haptoglobulin dropped to less than 50 mg%. In 3 recipients increased levels of isohemagglutinin IgG titers were observed. The pts. were treated successfully with multiple RBC transfusions, fluids, diuretics, plasma exchange, high dose immunoglobulins, steroids and erythropoietin. Since NST achieves a state of mixed chimerism without ablation of the recipients' B cell response to RBC-mismatched antigens, we conclude that as it may be associated with an increased risk of delayed hemolysis.

Detection of soluble HLA-G levels in maternal serum can be predictive for a successful pregnancy

THE IDENTIFICATION of HLA-G on placental cytotrophoblast cells opened new insights in defining the initial trigger by which the maternal immune system recognizes the fetal allograft and emits growth signals to the feto-placental unit. The presence of an alternatively spliced mRNA giving rise to secreted HLA-G class I antigens makes these molecules very important candidates for explaining peripheral maternal immunostimulation and immunosuppression during pregnancy. In many cases, especially during transplantation, soluble MHC antigens have been shown to exert immunosuppressive activity. Therefore, during pregnancy, the maternal organism is expected to respond to the semior fully allogeneic fetus in a similar way, where soluble antigens during the first 2 months of gestation elaborate messages that are positive to fetal growth (immunostimulation) and thereafter, equilibrates fetal development by inducing specific immunosuppression. Disability of the maternal organism to elaborate these two types of reaction results in embryo loss, mainly during the first trimester of pregnancy, which in previous studies has been correlated with expression of class II MHC antigens on trophoblasts, normally absent from these cells throughout pregnancy. In the present study, using the monomorphic W6/32 and 7H3 antibodies, we define the levels of soluble HLA-G and HLA-DR respectively in the serum of healthy women before, during, and after pregnancy and compare them to cases of first-trimester fetal abortions of unknown etiology. Taking into consideration the obtained results, along with similar findings from animal experimental abortion models, we conclude that the levels of soluble class I/II in the maternal serum can be predictive to a successful pregnancy outcome.

Intracerebroventricular injection of interleukin-1 suppresses peripheral lymphocyte function in the primate.

The cytokine interleukin-1 (IL-1) can act within the brain to induce peripheral endocrine and immune effects. In the rodent intracerebroventricular (i.c.v.) injection of IL-1 activates the hypothalamic-pituitary-adrenal axis and suppresses peripheral immune function by a CRH-dependent mechanism. It is unknown if IL-1 can similarly act within the brain to cause peripheral immunosuppression in the primate and to what extent this could be attributed to the IL-1-induced increase in ACTH and cortisol levels. In this study we have characterized the pituitary-adrenal and peripheral lymphocyte responses to IL-1 alpha (4.2 micrograms) infused over 30 min into the lateral ventricle of ovariectomized monkeys (n = 5) as compared with responses to an intravenous (i.v.) ACTH infusion (1 microgram/h for 7 h; n = 4). Four serial blood samples were obtained for ACTH and cortisol determination and for lymphocyte isolation during a 1-hour baseline and for 7 h after IL-1 or ACTH. Lymphocyte proliferation was measured by 3H-thymidine uptake in response to stimulation with phytohemagglutinin. In all 5 animals, IL-1 alpha caused rapid and profound suppression of lymphocyte mitogen responsiveness for 7 h. Baseline lymphocyte proliferation was 51,800 +/- 9,780 cpm and suppressed to a nadir of 4.5% with a mean of 23% baseline over 7 h (p < 0.001). Mean ACTH and cortisol levels increased from 33 +/- (SEM) 4.6 pg/ml and 43 +/- 4.0 micrograms/dl, respectively, during the control period to 90 +/- 14 pg/ml and 56 +/- 2.6 micrograms/dl, respectively, after IL-1 (p < 0.01). Before i.v. ACTH, baseline lymphocyte proliferation was 49,400 +/- 2,820 cpm, and suppressed to a mean of 64% of baseline during ACTH infusion (p < 0.05). Mean ACTH and cortisol levels increased from 48 +/- 5.0 pg/ml and 43 +/- 2.0 micrograms/dl, respectively, to 170 +/- 34 pg/ml and 66 +/- 2.3 micrograms/dl, respectively, during the ACTH infusion (p < 0.01). Lymphocyte suppression after i.c.v. IL-1 was much more profound than after i.v. ACTH (p < 0.01); the area under the IL-1 response curve was 37% of the area under the ACTH response curve. These studies demonstrate for the first time in the primate that centrally injected IL-1 has a profound suppressive effect on lymphocyte function. They also show for the first time in any species that there appears to be a significant immunosuppressive message produced by i.c.v. IL-1 that is not accounted for by the associated increases in ACTH and cortisol.

Hematopoietic alterations after exposure to T-2 mycotoxin

Adult mice were exposed by oral gavage to 0.75, 1.25, or 1.75 mg/kg body weight T-2 mycotoxin for 5 consecutive days. Thymic atrophy on the 2nd day following cessation of dosing was profound, and was characterized by significant decreases in the total number of cells within all phenotypes defined by CD4 and CD8 cell-surface antigen expression. Further, the distribution of thymocytes within these phenotypes was significantly altered. Increased percentages of CD4 −8 − (DN) and decreased percentages of CD4 +8 + (DP) cells in thymuses from treated animals suggested that T-2 toxin may inhibit thymocyte maturation. In addition to thymus, the bone marrow of treated animals showed a highly significant hypocellularity, indicating that this hematopoietic compartment may also be targeted by T-2 toxin. A trend toward reduced splenic cellularity was additionally observed in exposed animals, but failed to reach significance. A significant decrease in the total number of both B and T-lymphocytes present within the spleen was observed, however. These data, taken together, indicate that effects at multiple hematopoietic compartments involved in the production of T-lymphocytes may contribute to the peripheral T-cell lymphocytopenia and T-cell mediated immunosuppression produced by T-2 toxin.

8.7-01 Correlation between binding of cyclosporine metabolites to peripheral blood mononuclear cells and immunosuppression in vitro

8.7-01 Correlation between binding of cyclosporine metabolites to peripheral blood mononuclear cells and immunosuppression in vitro